Typically, methods for the synthesis of large numbers of diverse compounds involve successive chemical modifications of existing molecules. Modifications can include the addition of a chemical unit to a growing sequence or modification of a functional group. Chemical units can take many forms, both naturally-occurring and synthetic, including compounds containing reactive functional groups such as neculeophiles, electrophiles, dienes, alkylating agents, acylating agents, diamines, nucleotides, amino acids, sugars, lipids or derivatives thereof, organic monomers, synthons, and combinations thereof. Alternatively, reactions can be involved which result in alkylation, acylation, nitration, halogenation, oxidation, reduction, hydrolysis, substitution, elimination, addition, and the like. This process can produce non-oligomers, oligomers, or combinations thereof in extremely small amounts, where the reaction history, and composition in appropriate cases, can be defined by the present tags. Non-oligomers include a wide variety of organic molecules, e.g., heterocyclics, aromatics, alicyclic, aliphatics and combinations thereof, such as steroids, antibiotics, enzyme inhibitors, ligands, hormones, drugs, alkaloids, opioids, terpenes, porphytins, toxins, catalysts, as well as combinations thereof. Oligomers include oligopeptides, olionucleotides, oligosaccharides, polylipids, polyesters, polyamides, polyurethanes, polyethers, poly (phosphorus derivatives) e.g., phosphates, phosphonates, phosphoramides, phosphonamides, phosphites, phosphinamides, etc., poly (sulfur derivatives) e.a., sulfones, sulfonates, sulfites, sulfonamides, sulfenamides, etc., where for the phosphorous and sulfur derivatives the indicated heteroatom for the most part will be bonded to C, H, N, O and combinations thereof.
Reactions can involve modifications at a variety of random sites of a central core molecular structure or modifications at specific sites. For example, one can brominate a polycyclic compound, where bromination can occur at a plurality of sites or use a brominating agent which will be specific for a particular site, e.g., N-bromosuccinimide. Typically, reactions will involve single sites or equivalent sites, for example, one of two hydroxyl groups of a glycol. For the most part, the subject synthesis will have at least two stages where other than bifunctional compounds are attached using the same linking functionality, e.g., amino acids and amide bonds, nucleotides and phosphate ester bonds, or mimetic compounds thereof, e.g., aminosocyanates and urea bonds.
The synthetic strategies will vary with the nature of the group of products one wishes to produce. Thus, the strategy must take into consideration the ability to change the nature of the product, while allowing for retention of the results of the previous stages and anticipating needs for the future stages. Where the various units are of the same family, such as nucleotides, amino acids and sugars, the synthetic strategies are relatively well-established and frequently conventional chemistry will be available. Thus, for nucleotides, phosphoramidite or phosphite chemistries can be employed; for oligopeptides, fluorenylmethyl (Fmoc), t-butyoxycarbonyl (Boc), etc. protection chemistries can be employed; for sugars, the strategies can be less conventional but a large number of protective groups, reactive functionalities, and conditions have been established for the synthesis of polysaccharides. For other types of chemistries, one will look to the nature of the individual unit and either synthetic opportunities will be known or will be devised, as appropriate.
Techniques have recently been developed wherein individual units are added sequentially in a controlled or random manner to produce all or a substantial proportion of possible compounds resulting from the different choices possible at each sequential stage in the synthesis. One disadvantage is that individual compounds are present only in minute amounts. While the biological activity of a given compound can be determined, the chemical structure of that particular compound cannot necessarily be determined. It is necessary for compounds made by such techniques to be amenable to methods for determining their composition.
There is a substantial interest in discovering methods for producing compounds which are not limited to sequential addition of like moieties, but frequently involve a multi-stage synthesis in which the reagents and/or conditions are varied to provide a variety of compounds. There needs to be, however, convenient ways to identify the structures of the large number of compounds which result from a wide variety of different modifications. Thus, there is a need to record the reaction history or the structures of the compound identified.
As the size of compound libraries increases, existing means for elucidating structure and segregating products introduce substantial inefficiencies and uncertainties that hinder accurate structure determination. Thus, there is a substantial need for new methods which will permit the synthesis of complex combinatorial chemical libraries, which readily permit accurate structural determination of individual compounds within the library which are identified as being of interest.